DESCRIPTION: (Applicant's Abstract) Cocaine abuse remain a serious problem in American society. Although the past decade has witnessed increased understanding of many aspects of cocaine's pharmacological effects, knowledge of cellular and molecular consequences of cocaine addiction is lacking. To address this deficiency, alterations in neuronal processes that accompany cocaine addiction and withdrawal in appropriate animal models must be identified. The present application seeks to continue studies regarding the neurophysiological effects of acute and chronic cocaine administration on the mesoaccumbens dopamine (DA) system thought to mediate cocaine's psychomotor stimulant and reinforcing properties. Experiments are proposed that should identify cellular and molecular alterations in ventral tegmental area (VTA) and nucleus accumbens (NAc) neurons after repeated cocaine treatment and withdrawal. Cocaine sensitization and self-administration will be used as an index of underlying neuroadaptations. Three neurophysiological techniques will be used: in vivo extracellular single cell recording, intracellular recordings from VTA slices, and whole-cell (or cell-attached) patch-clamp recordings from acutely dissociated adult VTA DA and NAc neurons. There are three specific aims: 1: To identify mechanisms underlying the induction of cocaine sensitization within the VTA. Sensitization may be initiated by an increase in the basal activity of VTA DA neurons. It is hypothesized that several cellular changes are involved, primarily DA D2 autoreceptor (AR) subsensitivity and excitatory amino acid receptor (EAAR) sensitization, but perhaps also changes in presynaptic DA D1 receptor (D1R) regulation of afferent inputs and altered serotonin (5-HT) transmission. 2: To identify mechanisms underlying the expression and maintenance of cocaine sensitization within the NAc. Previous studies indicate apparent D1R supersensitivity and EAAR subsensitivity accompanying sensitization. But there is also a marked decrease in neuronal excitability that might result from alterations in membrane sodium conductance induced by a D1R-cAMP-protein kinase A-mediated phosphorylation of sodium channels. A series of mechanistic studies will test this hypothesis and will identify other possible receptor and transduction changes. Potential differences between core and shell regions of the NAc will also be examined. 3: To determine neurophysiological adaptations relevant to cocaine self-administration and withdrawal. Recent investigations have demonstrated marked differences in certain effects of self-administered and noncontingently received cocaine. These differences may be particularly relevant to cocaine addiction, withdrawal and relapse. This specific aim seeks to establish the intravenous self-administration procedure in our laboratory such that in vitro neurophysiological approaches can be used to study VTA DA and NAc neurons from rats that received cocaine via self-administration and those that received it non-contingently (yoked controls). Rats will be tested immediately after self-administration and at withdrawal times that are associated with behavioral depression and anhedonia. It is hypothesized that these different forms of cocaine administration will result in distinct forms of plasticity due to learned associations that result in changes in afferent inputs to the VTA and NAc. The results from these studies should help to identify relevant neuroadaptations that could aid in the development of better treatment approaches for cocaine addiction.